Abstract
Mitochondrial dysfunction lies behind many neurodegenerative disorders, owing largely to the intense energy requirements of most neurons. Such mitochondrial dysfunction may work through a variety of mechanisms, from direct disruption of the electron transport chain to abnormal mitochondrial biogenesis. Recently, we have identified biallelic mutations in the mitochondrial flavoprotein “ferredoxin reductase” (FDXR) gene as a novel cause of mitochondriopathy, peripheral neuropathy, and optic atrophy. In this report, we expand upon those results by describing two new cases of disease-causing FDXR variants in patients with variable severity of phenotypes, including evidence of an inflammatory response in brain autopsy. To investigate the underlying pathogenesis, we examined neurodegeneration in a mouse model. We found that Fdxr mutant mouse brain tissues share pathological changes similar to those seen in patient autopsy material, including increased astrocytes. Furthermore, we show that these abnormalities are associated with increased levels of markers for both neurodegeneration and gliosis, with the latter implying inflammation as a major factor in the pathology of Fdxr mutations. These data provide further insight into the pathogenic mechanism of FDXR-mediated central neuropathy, and suggest an avenue for mechanistic studies that will ultimately inform treatment.
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Acknowledgements
We thank the patient families for their participation in this study. We also thank Jun-Song Mo, Geogianne M. Ciraolo and Tilat Rizvi and Jun-Song Mo at Cincinnati Children’s Hospital for their help obtaining the electron microscopy images. This work was supported in part by Cincinnati Children’s Hospital Research Foundation and National Eye Institute (1R01EY026609-01 awarded to TH). Animal studies were supported by in part by The Jackson Laboratory and by the NIH Office of Research Infrastructure Programs (R24 OD021325-01 awarded to L.G.R).
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The authors declare no conflict of interest. A.C. is a full-time employee of Ambry Genetics.
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Slone, J., Peng, Y., Chamberlin, A. et al. Biallelic mutations in FDXR cause neurodegeneration associated with inflammation. J Hum Genet 63, 1211–1222 (2018). https://doi.org/10.1038/s10038-018-0515-y
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DOI: https://doi.org/10.1038/s10038-018-0515-y
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